SOMATIC DELIVERY OF CATECHOLAMINES IN THE STRIATUM ATTENUATE PARKINSONIAN SYMPTOMS AND WIDEN THE THERAPEUTIC WINDOW OF ORAL SINEMET IN RATS

Guidelines for clinical transplantation studies for Parkinson's diseas e emphasize that transplants should be considered as all adjunct to sy stemic L-DOPA, yet few preclinical studies have specifically assessed the potential of transplants as an adjunct to the clinical gold standa rd treatment. The objectives of the present study were to determine if encapsulated PC12 cells implanted in rats with severe unilateral dopa mine depletions: (i) have a direct therapeutic effect on measures of p arkinsonian symptoms; and/or (ii) increase the therapeutic window of o ral sinemet ill this model. Rats with severe unilateral dopamine deple tions received striatal implants of encapsulated PC12 cells producing dopamine and L-DOPA, These rats were tested on a battery of behavioral measures of parkinsonian symptoms, at a range of doses of oral sineme t (0, 12, 24, and 36 mg/kg). Stereotypies/dyskinesias were also quanti fied after high doses of oral sinemet (36 and 50 mg/kg). The results c onfirm that parkinsonian symptoms call be quantified in rats with seve re dopamine depletions, and the validity and clinical relevance of the se measures are supported by the fact that the clinical gold standard treatment, oral sinemet, attenuates these parkinsonian symptoms. Somat ic delivery of dopamine and L-DOPA, directly to the dopamine-depleted striatum, also attenuates parkinsonian symptoms, In fact, the magnitud e of the therapeutic effect produced by continuous, site-specific, som atic delivery of dopamine and L-DOPA was larger than the effect produc ed by acute, systemic, oral sinemet. The beneficial effects of oral si nemet and striatal implants of catecholamine-producing devices were ad ditive, but there were no adverse effects related to stria tal catecho lamine-producing devices, and these devices did not increase the adver se effects related to oral sinemet. Therefore, striatal implants of ca techolamine-producing devices have direct therapeutic effects which ar e fairly robust, and they widen the therapeutic window of oral sinemet . (C) 1997 Academic Press.